盐酸右美托咪定对2-氯乙基乙基硫醚致人支气管上皮细胞损伤的保护作用及机制

doi:10.3969/j.issn.1004-616x.2024.05.002

癌变·畸变·突变 ›› 2024, Vol. 36 ›› Issue (5): 342-348,358.doi: 10.3969/j.issn.1004-616x.2024.05.002

• 论著 • 上一篇

盐酸右美托咪定对2-氯乙基乙基硫醚致人支气管上皮细胞损伤的保护作用及机制

师敏婕^1,2, 李嘉³, 邓紫丰¹, 詹天豪¹, 刘建豪¹, 赵昱舜¹, 李文丽¹, 刘江正¹, 孔德钦¹

1. 空军军医大学军事预防医学系军事毒理学与防化医学教研室, 特殊作业环境危害评估与防治教育部重点实验室, 陕西省自由基生物学与医学重点实验室, 陕西西安 710032;
2. 陕西中医药大学公共卫生学院, 陕西西安 712046;
3. 空军军医大学航空航天医学系飞行人员康复与疗养教研室, 陕西西安 710032

收稿日期:2024-05-09 修回日期:2024-09-02 发布日期:2024-10-15
通讯作者: 刘江正, 孔德钦
作者简介:师敏婕,E-mail:419162645@qq.com。
基金资助:
国家自然科学基金(32100996),陕西省重点研发计划(2023-YBSF-297)

Mechanism of dexmedetomidine hydrochloride on 2-chloroethyl ethyl sulfide-induced injury in human bronchial epithelial cells

SHI Minjie^1,2, LI Jia³, DENG Zifeng¹, ZHAN Tianhao¹, LIU Jianhao¹, ZHAO Yushun¹, LI Wenli¹, LIU Jiangzheng¹, KONG Deqin¹

1. Department of Military Toxicology and Chemical Defense Medicine, School of Military Preventive Medicine, Air Force Medical University; Key Laboratory of Free Radical Biology and Medicine of Shaanxi Province; Key Laboratory of Environmental Hazard Assessment and Prevention of Special Operations of Ministry of Education, Xi'an 710032;
2. School of Public Health, Shaanxi University of Chinese Medicine, Xi'an 712046;
3. Department of Recuperation and Rehabilitation for Flight Personnel, School of Aerospace Medicine, Air Force Medical University, Xi'an 710032, Shaanxi, China

Received:2024-05-09 Revised:2024-09-02 Published:2024-10-15

摘要/Abstract

摘要： 目的： 研究盐酸右美托咪定(DEX)对糜烂性毒剂2-氯乙基乙基硫醚(CEES)诱导的人支气管上皮细胞损伤的潜在保护作用及机制。方法： 使用浓度为1.2 mmol/L的CEES处理BEAS-2B细胞24 h，构建糜烂性毒剂导致细胞损伤的模型。使用不同浓度(0.1~1 000 μmol/L)的DEX预处理BEAS-2B细胞2 h后加CEES染毒24 h，再用CCK-8法检测细胞活力。选择DEX最佳保护剂量，在光镜下观察细胞形态，使用Annexin V/PI双染法检测细胞凋亡率，DHE、MitoSOX和RHOD123荧光探针分别检测细胞内总活性氧(ROS)、线粒体ROS (mtROS)和线粒体膜电位水平，通过试剂盒检测总超氧化物歧化酶(SOD)、CuZn-SOD、Mn-SOD酶活性和-谷胱甘肽(GSH)含量变化。结果： 与对照组相比，CEES染毒组细胞活力均明显降低(P<0.01)，凋亡细胞数显著升高(P<0.01)，细胞内总ROS、mtROS水平均明显升高(P<0.01)，线粒体膜电位显著降低(P<0.01)，总SOD、CuZn-SOD、Mn-SOD酶活性均升高(P<0.01)，GSH含量降低(P<0.01)。与CEES染毒组相比，0.1~1 000 μmol/L DEX干预组细胞活力均升高(P<0.01)，其中10 μmol/L DEX干预组细胞活力升高最明显(P<0.01)，后续用10 μmol/L作为DEX干预组的最佳剂量。使用10 μmol/L DEX干预显著抑制了CEES诱导的细胞凋亡(P<0.01)，DEX干预组ROS和mtROS均降低(P<0.01)，线粒体膜电位升高(P<0.05)，总SOD、CuZn-SOD酶活力升高(P<0.01)，GSH含量升高(P<0.01)。结论： DEX对CEES导致的人支气管上皮细胞损伤具有保护作用，其机制可能与调控线粒体稳态、降低mtROS的产生及增强细胞抗氧化水平有关。

关键词: 糜烂性毒剂, 盐酸右美托咪定, 线粒体, 氧化应激, 活性氧

Abstract: OBJECTIVE： To investigate protective effect and mechanism of dexmedetomidine hydrochloride (DEX) on blister agent 2-chloroethyl ethyl sulfide (CEES)-induced injury in human bronchial epithelial cells. METHODS： BEAS-2B cells were exposed to 1.2 mmol/L CEES for 24 h to establish a cell damage model induced by blister agents. The cells were pretreated with various concentrations of DEX for 2 h and exposed to CEES for 24 h. Cell viability was detected by the CCK-8 method to determine the optimal protective dose of DEX. Cell morphology was observed under a light microscope，and cell apoptosis rates were measured using Annexin V/PI staining. DHE，MitoSOX and RHOD123 fluorescent probes were employed to detect total reactive oxygen species (ROS)，mitochondrial ROS (mtROS) and mitochondrial membrane potential levels，respectively. Enzyme activities of total SOD，CuZn-SOD and Mn-SOD and content of GSH were detected by kits. RESULTS： Compared with the control group，the CEES group showed a significant decrease in cell viability (P<0.01)，a significant increase in cell apoptosis (P<0.01)，a significant increase in ROS and mtROS (P<0.01)，a significant decrease in mitochondrial membrane potential (P<0.01)，an increase in total SOD，CuZn-SOD and Mn-SOD enzyme activity (P<0.01)，and a decrease in GSH content (P<0.01). Compared with the CEES group，the cell viability of 0.1-1 000 μmol/L DEX intervention group was increased，and the most significant increase in cell viability was observed in the 10 μmol/L DEX intervention group (P<0.01)，and 10 μmol/L was used as the optimal dose for the follow DEX intervention group. Apoptosis was decreased after the 10 μmol/L DEX intervention (P<0.01). Compared with the CEES treatment group，DEX intervention reduced mtROS (P<0.01)，increased mitochondrial membrane potential (P<0.05)，increased enzyme activity of total SOD and CuZn-SOD (P<0.01)，and increased GSH content (P<0.01). CONCLUSION： DEX exerted a protective effect on CEES-induced injury in human bronchial epithelial cells，and its mechanism could be related to the regulation of mitochondrial homeostasis，the reduction of mtROS production and the enhancement of cellular antioxidant levels.

Key words: blister agents, dexmedetomidine hydrochloride, mitochondria, oxidative stress, reactive oxygen species

中图分类号:

R858.5

师敏婕, 李嘉, 邓紫丰, 詹天豪, 刘建豪, 赵昱舜, 李文丽, 刘江正, 孔德钦. 盐酸右美托咪定对2-氯乙基乙基硫醚致人支气管上皮细胞损伤的保护作用及机制[J]. 癌变·畸变·突变, 2024, 36(5): 342-348,358.

SHI Minjie, LI Jia, DENG Zifeng, ZHAN Tianhao, LIU Jianhao, ZHAO Yushun, LI Wenli, LIU Jiangzheng, KONG Deqin. Mechanism of dexmedetomidine hydrochloride on 2-chloroethyl ethyl sulfide-induced injury in human bronchial epithelial cells[J]. Carcinogenesis, Teratogenesis & Mutagenesis, 2024, 36(5): 342-348,358.

参考文献

[1] KHATERI S, GHANEI M, KESHAVARZ S, et al. Incidence of lung, eye, and skin lesions as late complications in 34, 000 Iranians with wartime exposure to mustard agent[J]. J Occup Environ Med, 2003, 45(11): 1136-1143.
[2] OJHA S, ABRAMSON J, DORLING J. Sedation and analgesia from prolonged pain and stress during mechanical ventilation in preterm infants: is dexmedetomidine an alternative to current practice-[J]. BMJ Paediatr Open, 2022, 6(1): e001460.
[3] 刘云, 杨旭东. 右美托咪定肺保护作用的研究进展[J]. 中国口腔医学继续教育杂志, 2023, 26(6): 442-448.
[4] SHI J, YU T X, SONG K, et al. Dexmedetomidine ameliorates endotoxin-induced acute lung injury in vivo and in vitro by preserving mitochondrial dynamic equilibrium through the HIF-1a/HO-1 signaling pathway[J]. Redox Biol, 2021, 41: 101954.
[5] KARABULUT G, BEDIRLI N, AKYüREK N, et al. Dose-related effects of dexmedetomidine on sepsis-initiated lung injury in rats[J]. Braz J Anesthesiol, 2021, 71(3): 271-277.
[6] BAI Y X, ZHANG J H, ZHAO B C, et al. Dexmedetomidine attenuates one-lung ventilation associated lung injury by suppressing inflammatory responses: a systematic review and meta-analysis[J]. Clin Exp Pharmacol Physiol, 2021, 48(9): 1203-1214.
[7] WANG X, ZHANG B, LI G Q, et al. Dexmedetomidine alleviates lung oxidative stress injury induced by ischemia-reperfusion in diabetic rats via the Nrf2-Sulfiredoxin1 pathway[J]. Biomed Res Int, 2022, 2022: 5584733.
[8] LIU T, SUN L, ZHANG Y B, et al. Imbalanced GSH/ROS and sequential cell death[J]. J Biochem Mol Toxicol, 2022, 36(1): e22942.
[9] WATANABE K, SHIBUYA S, OZAWA Y, et al. Pathological relationship between intracellular superoxide metabolism and p53 signaling in mice[J]. Int J Mol Sci, 2021, 22(7): 3548.
[10] HAN D W, OH J E, LIM B J, et al. Dexmedetomidine attenuates subarachnoid hemorrhage-induced acute lung injury through regulating autophagy and TLR/NFκB signaling pathway[J]. Korean J Anesthesiol, 2022, 75(6): 518-529.
[11] SABNAM S, RIZWAN H, PAL S, et al. CEES-induced ROS accumulation regulates mitochondrial complications and inflammatory response in keratinocytes[J]. Chem Biol Interact, 2020, 321: 109031.
[12] 龚楚楚. MiR-199a-5p在人脐带间充质干细胞来源的外泌体改善芥子气肺损伤中的作用与机制[D]. 上海: 中国人民解放军海军军医大学, 2022.
[13] MARIAPPAN N, HUSAIN M, ZAFAR I, et al. Extracellular nucleic acid scavenging rescues rats from sulfur mustard analog-induced lung injury and mortality[J]. Arch Toxicol, 2020, 94(4): 1321-1334.
[14] 丁允莹, 嵇富海, 彭科. 右美托咪定的器官保护作用及其机制概述[J]. 解放军医学杂志, 2023, 48(11): 1267-1275.
[15] 吴新民, 薛张纲, 马虹, 等. 右美托咪定临床应用专家共识(2018)[J]. 临床麻醉学杂志, 2018, 34(8): 820-823.
[16] SONG K, SHI J, ZHAN L N, et al. Dexmedetomidine modulates mitochondrial dynamics to protect against endotoxin-induced lung injury via the protein kinase C-ɑ/haem oxygenase-1 signalling pathway[J]. Biomarkers, 2022, 27(2): 159-168.
[17] AMINI H, SOLAYMANI-DODARAN M, MOUSAVI B, et al. Long-term health outcomes among survivors exposed to sulfur mustard in Iran[J]. JAMA Netw Open, 2020, 3(12): e2028894.
[18] ANDRES D K, KEYSER B M, MELBER A A, et al. Apoptotic cell death in rat lung following mustard gas inhalation[J]. Am J Physiol Lung Cell Mol Physiol, 2017, 312(6): L959-L968.
[19] 孔德钦, 刘思佳, 刘建豪, 等. 肝细胞核因子-1b在糜烂性毒剂2-氯乙基乙基硫醚诱导急性肺支气管上皮细胞损伤中的作用及其机制[J]. 癌变·畸变·突变, 2024, 36(1): 1-8.
[20] 原杨, 尚悦, 王鹏, 等. 基于斑马鱼模型的中药致肝脏毒性评价的研究进展[J]. 药物评价研究, 2024, 47(5): 933-940.
[21] 夏延贞, 王龙珍, 莫靓, 等. 右美托咪定通过lncRNA H19介导香烟提取物诱导的肺泡巨噬细胞效应研究[J]. 毒理学杂志, 2021, 35(1): 56-60, 66.
[22] MORANA O, WOOD W, GREGORY C D. The apoptosis paradox in cancer[J]. Int J Mol Sci, 2022, 23(3): 1328.
[23] LAM T Y W, NGUYEN N, PEH H Y, et al. ISM1 protects lung homeostasis via cell-surface GRP78-mediated alveolar macrophage apoptosis[J]. Proc Natl Acad Sci U S A, 2022, 119(4): e2019161119.
[24] HONG J G, CHEN Q M, WANG Y B, et al. Dexmedetomidine alleviates smoke-induced bronchial and alveolar epithelial cell injury[J]. Gen Physiol Biophys, 2020, 39(3): 293-300.
[25] CUI H B, ZHANG Q. Dexmedetomidine ameliorates lipopolysaccharide-induced acute lung injury by inhibiting the PI3K/Akt/FoxO1 signaling pathway[J]. J Anesth, 2021, 35(3): 394-404.
[26] BRILLO V, CHIEREGATO L, LEANZA L, et al. Mitochondrial dynamics, ROS, and cell signaling: a blended overview[J]. Life, 2021, 11(4): 332.
[27] JIANG Y, KRANTZ S, QIN X, et al. Caveolin-1 controls mitochondrial damage and ROS production by regulating fission - fusion dynamics and mitophagy[J]. Redox Biol, 2022, 52: 102304.
[28] LI Z H, PAN H T, YANG J H, et al. Xuanfei Baidu formula alleviates impaired mitochondrial dynamics and activated NLRP3 inflammasome by repressing NF-κB and MAPK pathways in LPS-induced ALI and inflammation models[J]. Phytomedicine, 2023, 108: 154545.
[29] LIU M L, WU X, CUI Y L, et al. Mitophagy and apoptosis mediated by ROS participate in AlCl₃-induced MC3T3-E1 cell dysfunction[J]. Food Chem Toxicol, 2021, 155: 112388.
[30] ZAIB S, HAYYAT A, ALI, et al. Role of mitochondrial membrane potential and lactate dehydrogenase A in apoptosis[J]. Anticancer Agents Med Chem, 2022, 22(11): 2048-2062.
[31] AL-ZUBAIDI U, LIU J, CINAR O, et al. The spatio-temporal dynamics of mitochondrial membrane potential during oocyte maturation[J]. Mol Hum Reprod, 2019, 25(11): 695-705.
[32] WANG L, DING Y L, BAI Y H, et al. The activation of SIRT3 by dexmedetomidine mitigates limb ischemia-reperfusion-induced lung injury[J]. Ann Transl Med, 2022, 10(6): 319.
[33] XU J J, LEI S Q, YE G. Dexmedetomidine attenuates oxidative/nitrative stress in lung tissues of septic mice partly via activating heme oxygenase-1[J]. Exp Ther Med, 2019, 18(4): 3071-3077.
[34] CHEN Y Y, HUANG Y, XIONG B R, et al. Dexmedetomidine ameliorates renal ischemia reperfusion-mediated activation of the NLRP3 inflammasome in alveolar macrophages[J]. Gene, 2020, 758: 144973.
[35] SHI F Q, ZHANG Z H, CUI H N, et al. Analysis by transcriptomics and metabolomics for the proliferation inhibition and dysfunction through redox imbalance-mediated DNA damage response and ferroptosis in male reproduction of mice and TM4 Sertoli cells exposed to PM_2.5[J]. Ecotoxicol Environ Saf, 2022, 238: 113569.
[36] 姜晓旭, 孙慕涵, 张渤旭, 等. 特女贞苷对脂多糖诱导的巨噬细胞促炎反应的抑制作用及机制[J]. 癌变·畸变·突变, 2023, 35(4): 245-252.

盐酸右美托咪定对2-氯乙基乙基硫醚致人支气管上皮细胞损伤的保护作用及机制

Mechanism of dexmedetomidine hydrochloride on 2-chloroethyl ethyl sulfide-induced injury in human bronchial epithelial cells

PDF

可视化

摘要/Abstract

引用本文

使用本文

参考文献

相关文章 15

编辑推荐

Metrics

本文评价

[1]	李佳威, 郭晓洁, 师敏婕, 李文丽, 刘江正. 雾化吸入NaClO致小鼠肺损伤模型的构建及机制研究[J]. 癌变·畸变·突变, 2024, 36(4): 281-287,297.
[2]	孙鑫, 李爽, 陆雪, 蔡恬静, 刘雅, 刘青杰, 张伟. 低剂量电离辐射对人淋巴细胞氧化应激及DNA损伤的影响[J]. 癌变·畸变·突变, 2024, 36(2): 94-99.
[3]	孔德钦, 刘思佳, 刘建豪, 马耀, 马丞飞, 赵昱舜, 周嘉恒, 师敏婕, 李嘉, 刘江正. 肝细胞核因子-1b在糜烂性毒剂2-氯乙基乙基硫醚诱导急性肺支气管上皮细胞损伤中的作用及其机制[J]. 癌变·畸变·突变, 2024, 36(1): 1-8.
[4]	康真, 于天一, 刘晓波, 洪千淇, 蔡书锐, 闫海. 苯并[b]荧蒽和二苯并[a,h]蒽对成年雄性大鼠氧化应激和炎症因子的影响[J]. 癌变·畸变·突变, 2024, 36(1): 16-20.
[5]	李雪梅, 康萌, 万静之, 李澳忠, 刘启玲, 秦绪军. 酒精性肝病中的铁死亡机制研究进展[J]. 癌变·畸变·突变, 2024, 36(1): 66-69,76.
[6]	林鹏, 张璨, 杨玉, 杨光远, 刘明远. 枸杞多糖对Nrf2信号通路调控作用的研究进展[J]. 癌变·畸变·突变, 2024, 36(1): 77-79.
[7]	廖明星, 李仁燕. 镉诱导细胞焦亡相关机制的研究进展[J]. 癌变·畸变·突变, 2023, 35(6): 482-484,488.
[8]	高榴, 禹莉. 线粒体转录因子A在肿瘤发生发展中作用的研究进展[J]. 癌变·畸变·突变, 2023, 35(6): 485-488.
[9]	郭晓洁, 刘鹏晖, 龙子, 李佳威, 涂永梅, 李文丽, 刘启玲. 氧化应激致自噬在光气诱导的急性肺损伤中的作用[J]. 癌变·畸变·突变, 2023, 35(5): 325-333,340.
[10]	姜晓旭, 孙慕涵, 张渤旭, 王钰越, 马加骏, 师敏捷, 于卫华, 郭显. 特女贞苷对脂多糖诱导的巨噬细胞促炎反应的抑制作用及机制[J]. 癌变·畸变·突变, 2023, 35(4): 245-252.
[11]	王钊, 刘思佳, 刘建豪, 马丞飞, 赵昱舜, 徐安琦, 艾多, 戚羽佳, 孔德钦, 刘江正. 糜烂性毒剂氮芥染毒对肝细胞线粒体结构和功能的影响[J]. 癌变·畸变·突变, 2023, 35(2): 102-108,153.
[12]	蔡娇, 孔德钦, 龙子, 彭洁, 刘江正, 刘瑞, 海春旭. IRAK4在对乙酰氨基酚诱导的急性肝细胞损伤中的作用及其机制[J]. 癌变·畸变·突变, 2022, 34(4): 255-261.
[13]	赵晨茜, 徐安琦, 艾多, 孔德钦, 张晓迪, 李文丽, 海春旭, 刘江正. 线粒体靶向抗氧化剂Mito-TEMPO对氮芥诱导BEAS-2B细胞损伤的影响[J]. 癌变·畸变·突变, 2022, 34(3): 161-168.
[14]	段惠娟, 孙照刚, 郝卫东, 魏雪涛, 褚洪迁. 4种化学物质对HaCaT细胞氧化应激相关基因表达的影响[J]. 癌变·畸变·突变, 2022, 34(3): 192-199,205.
[15]	于婧, 冯丹丹, 潘文森. 桑黄素在脂多糖诱导的急性肺损伤中的相关机制[J]. 癌变·畸变·突变, 2022, 34(3): 213-218.